P-chiral Prodrugs
Nucleosides are an important class of drug accounting for many of the anti-viral and anti-cancer drugs currently on the market e.g. AZT (GSK), Cladribine (Janssen), Capecitabine (Roche), Zovirax (GSK), Gemzar (Lilly) etc.
In order to be effective, all nucleosides require metabolic activation in their target cell to the bio-active phosphate (“nucleotide”) form. However, this metabolic activation is often not very efficient and thus the therapeutic potential for these nucleosides is often quite limited. In addition, pre-formation of the phosphate generally speaking does not offer any advantage on account of poor permeation of the phosphate through the cell membrane.
This has led to a large body of work involving the use of so-called “pro-drugs” (A pro-drug is a pharmacological substance which is administered in an inactive form which once administered is metabolized in vivo to the active drug). One avenue of investigation has been to use phosphate pro-drugs and has become known as the “Protide” approach. One of the protide approaches which has proved particularly effective to date is the use of aryloxy phosphoramidates of the general structure shown below:
Effectively the phosphoramidate moiety is “clipped onto” the parent nucleoside. These phosphoramidate protides are often hundreds (and sometimes thousands) of times more potent than the parent nucleoside. Such compounds are currently under investigation by major pharmaceutical companies including Gilead, Roche and GSK. However despite their obvious therapeutic and commercial potential there is one considerable drawback which has inhibited the more widespread development of these compounds. This is related to the difficulties in development of a cost-effective synthesis of the active form of such protides.
When one examines the above structure carefully it is apparent that it is a P-chiral molecule – i.e. there is a chiral centre at the phosphorus atom, meaning that the groups attached to the phosphorus can exist in 2 possible configurations (i.e. 2 stereoisomers). Usually these isomers will have different properties in terms of potency, bioavailability, toxicity etc. Because of this, FDA regulations require each isomer to be tested in isolation. Because of the difference in properties (and hence difference in efficacy) of each of the isomers, generally speaking only one isomer graduates to becoming a viable clinical candidate.
However, to date manufacture of these isomer compounds at a large scale has required a very expensive methodology known as SMB (Simulated Moving Bed) Technology. SMB involves the synthesis of the mixture of isomers and subsequent separation. However, it can be appreciated that is extremely uneconomical because at least 50% of the active pharmaceutical ingredient goes to waste and in most cases cannot be recycled. This can add hugely to the manufacturing costs at the hundreds of kilogram or tonne scale. This very fact has heretofore hindered and discouraged researchers from investigating this class of compound in any meaningful way.
Celtic Catalysts are the world leaders in the development of P-chiral chemistry. We have developed revolutionary new synthetic pathways which allow the synthesis of just the required isomer of P-chiral molecules without the need to resort to wasteful separation of mixtures of isomers. Our patented technology and expertise can be applied to the synthesis of P-chiral protides of the type mentioned above. Thus the opportunity exists to significantly bolster the development pipelines of Pharma with an existing portfolio of nucleoside drugs in the anti-viral and anti-cancer areas. This can be achieved by attaching such phosphoramidate structures onto a range of existing nucleoside drugs and thus create New Chemical Entities (NCEs) which have a very high chance of clinical success, are far more potent and efficacious than the parent compounds - but crucially Celtic Catalysts technology will enable their large scale cost-effective manufacture.